Tenofovir induced Fanconi syndrome in a middle age African female from Kenya, East Africa: Case report and brief literature review

Key Clinical Message This case presentation highlights the need to routinely monitor renal function in patients on Tenofovir Disoproxil Fumarate (TDF) due to its side effect of proximal tubule dysfunction. Abstract This is a case presentation of a 50‐year‐old African female who had been on a Tenofovir based regimen for 12 years and developed Fanconi syndrome. She recovered after discontinuation of the Tenofovir Disoproxil Fumarate (TDF).


| INTRODUCTION
Tenofovir Disoproxil Fumarate (TDF) is one of the newest and more tolerable backbone of highly active antiretroviral therapy (HAART) in the class of nucleotide reverse transcriptase inhibitor (NRTI).In 2016, World Health Organization (WHO) published a consolidated guideline that recommended Tenofovir based regimen as the first line for adults and adolescents and henceforward this regimen has been extensively rolled out. 1 Despite its excellent safety profile and tolerability TDF is known to cause proximal tubule renal dysfunction.TDF renal tubulopathy can manifest as Fanconi syndrome (FS), Acute kidney injury or chronic kidney disease. 2 Here, we present the case of a middle age African female on Tenofovir based regimen who developed FS after 12 years of Tenofovir based HAART.

| CASE PRESENTATION
We present a case of a 50-year-old black African female on management of HIV for the last 12 years who presented to our hospital with complaints of longstanding generalized body aches and bone pains for a duration of 2 years.These symptoms got worse 3 weeks prior to admission and were associated with muscle weakness of both the upper and lower limbs.In addition, she had joint pains worsened by activity but not associated with stiffness.A year prior to admission she suffered a trivial fall without a fracture that rendered her unable to walk.She denied any of history of cough, weight loss, night sweats, back pain, or paraesthesia.Moreover, she had normal bladder and bowel control without polydipsia, polyuria or even polyphagia.
Our patient was initiated on HAART in 2011 and has been on her drugs with excellent adherence since then.
She was on TDF/3TC/EFV, however in 2019 she was transferred to TDF/3TC/DTG as part of a Nationwide optimization program.
She has a history of pulmonary TB treatment 13 years ago but no history of any other opportunistic infection, hypertension or diabetes.
General exams revealed a middle-aged female who was alert and responsive, groaning and moaning in pain.She was wasted with a BMI of 17.8 kg/m 2 and a weight of 48 kg.There was no pallor, jaundice, dehydration, oedema, or lymphadenopathy.Her vital signs were within the normal ranges.On musculoskeletal exams she had reduced muscle bulk, reduced muscle power graded at 3/5 and tenderness on palpation of the muscles and along the long bones.Range of motion of the right hip joint was also restricted.The other systemic exams were normal.

| METHODS
Laboratory investigations done at admission revealed reduced GFR at 35.80 mL/min/1.73m 2 (CKD-EPI) with raised creatinine levels of 152.58 umol/L.Her Calcium and Uric acid levels were low at 1.8 mmol/L and 2.26 mg/dL respectively.She had normal HBA 1c of 4.6% with a normal random blood sugar of 6.7 mmol/L and abnormal urinalysis findings that included glycosuria of 250 mg/dL, proteinuria of 100 mg/dL and urine pH of 7.0.She had normal full hemogram and electrolytes, and a negative Rheumatoid factor.Serum Protein Electrophoresis (SPEP) and Urine Protein Electrophoresis (UPEP) was normal with no paraproteinemia.
KUB ultrasound was normal, but the bone survey x-rays as depicted on Figure 1 and Figure 2, revealed features of osteoporosis.Pelvic Xray disclosed thinning of the cortical bone and loss of trabeculae especially at the proximal aspect of femur and skull Xray showed areas of radiolucency, all in keeping with osteoporosis.Renal biopsy was considered but due to financial constraints was not done.
A diagnosis of FS secondary to Tenofovir nephrotoxicity was made based on clinical symptoms of generalized body aches and bone pains and supporting laboratory findings of elevated creatinine levels, proteinuria, glycosuria, hypouricemia, osteoporosis, and a urine pH of >5.
Due to excellent adherence with undetectable viral load and cost implications on the patient, we stopped doing regular CD4 counts.CD4 cell count trends is depicted below on Table 1.

| CONCLUSION AND RESULTS
Our patient was then switched from TDF based regimen to an Abacavir based one, Abacavir/Lamivudine/ Dolutegravir.Serial creatinine levels were done, See Table 2.
She had progressive reduction in the creatinine levels and repeat of urinalysis 11 weeks later revealed clearance of the proteinuria and glycosuria, normal calcium levels of 2.25 mmol/L and improvement in muscle power and activities of daily living.She was now able to walk with support using a walker.

| DISCUSSION
TDF is largely renally excreted via active tubular secretion and glomerular filtration in its unchanged form with no interaction with the CYP450 pathway. 320%-30% of the drug is excreted via tubular secretion. 4The main mechanism of proximal tubular injury results from mitochondrial destruction following an imbalance between intracellular uptake and efflux of tenofovir 5 mediated by human organic anion transporters (hOAT) and multidrug resistance proteins (MRPs) respectively that leads to intracellular accumulation of TDF.A decreased glomerular filtration rate (GFR) has been shown to be associated with increased intracellular concentrations of TDF, through increased OAT1 activity.With intracellular toxicity, structural mitochondrial damage results from loss of mitochondrial proteins and DNA.The resultant mitochondrial depletion and dysfunction triggers apoptosis of the cell. 6S is a proximal tubule dysfunction that results in normoglycemic glycosuria, as well as urinary loss of phosphate, calcium, uric acid, amino acids, bicarbonates, and tubular proteins. 7Tenofovir can cause complete or partial FS.Majority of cases present as partial with an elevation in creatinine levels, hypophosphatemia, and glycosuria. 8atients on TDF based regimen are at five times greater risk of developing chronic kidney disease in comparison to patients on a non-TDF based regimen.This rapid decline of estimated GFR mostly occur in the first 2-3 years of treatment. 9The prevalence of renal dysfunction induced by TDF is estimated at 5.6%, and the risk is increased with advanced age, low BMI, low baseline CD4 count, hypertension, and diabetes. 10Severe nephrotoxicity to warrant discontinuation has been reported in 1% patients yearly. 11fricans with pre-existing renal disease and advanced age are at a greater risk of statistically significant TDF associated renal function decline. 12Concomitant protease inhibitor use has also been suggested to contribute to development of TDF associated nephrotoxicity. 13Other factors including low body weight and low CD4 cell count have been linked to increased susceptibility of TDF tubulopathy in some individuals. 14The diagnostic criteria for TDF related FS include normoglycemic glycosuria, proteinuria, and hypophosphatemia with phosphaturia 15 that can be screened for, through urine and blood tests.
Reliance on elevations in eGFR and urine albumin/creatinine ratio, may lead to missed diagnoses due to their poor sensitivity as markers of proximal tubular function. 16pproximately half of the patients attain partial or full recovery of renal function after 1 year of TDF discontinuation, defined as >70% of pre-TDF creatinine clearance with majority of major markers of proximal tubulopathy resolving within 8 weeks of drug discontinuation. 17owever, full reversibility of TDF -related renal toxicity is not always the rule. 18Early switching of TDF in patients with proximal renal tubulopathy has been associated with better chances of complete renal recovery as well as low levels of urine dipstick proteinuria at the time of discontinuation. 19his case illustrates a patient from an underserved region of a Low Middle-Income Country on Tenofovir based regimen for 12 years.She has excellent adherence as confirmed by the consistent undetectable viral load.However, she is unable to afford annual renal function tests as recommended by HAART guidelines. 8Renal function should be monitored prior to starting and throughout therapy as clinically appropriate, and caution should be taken with administering TDF with combination with other potentially nephrotoxic agents. 20HIV Medicine Association of the IDSA recommend at least biannual monitoring of renal function, serum phosphorus, proteinuria, and glycosuria in patients receiving tenofovir with GFR <90 mL/ min/1.73m 2 , other comorbid diseases or cotreated with protease inhibitors, due to the risk of nephrotoxicity. 13t follows a trivial fall with persistent and worsening body and bone pains that the patient gets to be admitted.Further work up revealed normoglycemic glycosuria, increase in creatinine with declining GFR, proteinuria, hypouricemia, hypocalcemia, and osteopenia.These laboratory findings are in keeping with FS where 5 out of 7 nondiabetic patients biopsied for Tenofovir nephrotoxicity had glycosuria with increased serum creatinine. 21nability to do Arterial Blood Gases (ABG) and phosphates in the resource limited regions further stifles the ability to clinch the diagnosis earlier. 22The bone pain and generalized body aches are possibly a consequence of osteomalacia, which is a late manifestation of proximal tubulopathy secondary to phosphate wasting and/calcitriol deficiency since calcitriol is synthesized by the mitochondria in the proximal tubules. 23About 40%-90% of HIV infected individuals experience low bone mineral density consistent with the diagnosis of osteopenia or osteoporosis. 24The cause of this multifactorial but antiretroviral toxicity, particularly TDF, has been implicated. 25Potential mechanisms of TDF toxicity on the bone can be due to direct or indirect effect.In vitro studies have demonstrated altered expression of genes involved in cell signaling, energy and amino acid metabolism in osteoclasts and osteoblasts exposed to physiological doses of TDF, a direct negative effect. 26Indirect effects are via renal/endocrine systems, severe tubulopathy due to TDF can result in bicarbonate and phosphate wasting that leads to osteomalacia and bone pain. 27DF may also affect vitamin metabolism directly driving a state of sustained hyperparathyroidism and increased bone turnover, in subjects on stable TDF containing ART, higher plasma TDF level have been associated with higher levels of vitamin D binding receptor leading to lower free 1, 25-hydroxy-vitamin D. 28 This "functional" deficiency can drive secondary hyperparathyroidism in patients on TDF containing regimens.Due to this there is therapeutic role for vitamin D3 supplementation at initiation of TDF containing ART to attenuate increase in PTH and reduction in bone mineral density.29 The proposed risk factors in this case includes and is not limited to prolonged TDF use, 30 low body weight and advanced age.14 The patient symptoms and renal function markedly improved following TDF discontinuation.6 weeks later, she had no glycosuria, proteinuria, hypocalcemia and had reduced creatinine levels.Alexandre Karras et al 31 reported that most of laboratory values in TDF tubulopathy returned to normal following its discontinuation.
In conclusion, we would like to emphasize the need for routine monitoring of renal function of patients on TDF based regimen for nephrotoxicity, even years after initiation of drugs.On any occasion TDF tubulopathy signs are recognized, the drug should be stopped to prevent further complications.

F I G U R E 1
Skull radiograph reveals areas of radiolucency.

F I G U R E 2 2
Pelvic radiograph reveals thinning of the cortical bone and loss of trabeculae especially at the proximal aspect of the femur.Creatinine trend.